Project Summary A central question in neuroscience is how sensory stimuli in the environment are represented. The olfactory system is an attractive sensory modality to approach this question since the major excitatory pathways that connect receptor neurons, second-order mitral cells in the olfactory bulb, and tertiary neurons in olfactory cortex and well understood. However, intracellular recordings demonstrate that neural representations of odors in second-order neurons (mitral and tufted cells) do not result exclusively from feedforward input from receptor cells. Instead, the output of the olfactory bulb results from complex interactions between excitatory and inhibitory circuits. Relatively little is known about the neural circuits that generate inhibition onto principal cells. The present proposal uses rodent brain slice recording methods to determine how local circuit pathways excite GABAergic olfactory bulb interneurons, inhibiting and shaping firing patterns in principal cells. Using both whole-cell intracellular recording and live 2-photon imaging methods, we will determine how the key synaptic pathways that enable sensory input to excite granule cells function and how they recruit intrinsic currents within granule cells. The proposal also will determine how inhibitory synaptic input to granule cells functions to modulation action potential discharges. Finally, the proposed work also will determine the functional role of a recently discovered form of long-term synaptic plasticity apparent in one class of these inputs. Defining the cellular mechanisms that generate sensory-evoked inhibition in the olfactory bulb, the overall focus of this proposal, is critical to understand how biological information is represented in the brain. The proposed studies also are significant as they represent an important step toward understanding the specific deficits in many major neurodegenerative diseases in which olfactory function is affected. In many of these diseases, sensory impairments occur early in the disease onset. Insights into the specific olfactory mechanisms affected in these diseases may lead to directly testable hypotheses regarding analogous mechanisms in the cortical areas responsible for the cognitive deficits commonly associated with neurodegenerative disorders.